Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia

• Type of Material: Article
• Authors: Fang Cao, University of Michigan; Elizabeth C. Townsend, University of Michigan; Hacer Karatas, University of Michigan; Jing Xu, University of Michigan; Li Li, Emory University; Shirley Lee, University of Michigan; Liu Liu, University of Michigan; Yong Chen, Chinese Academy of Sciences; Peter Ouillette, University of Michigan; Jidong Zhu, Chinese Academy of Sciences; Jay L. Hess, Indiana Univ Sch Med; Peter Atadja, Novartis Institutes for BioMedical Research, Shanghai; Ming Lei, Chinese Academy of Sciences; Zhaohui Qin, Emory University; Sami Malek, University of Michigan; Shaomeng Wang, University of Michigan; Yali Dou, University of Michigan
• Language: English
• Date: 2014-01-23
• Publisher: Elsevier Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2013.12.001
• Title of Journal or Parent Work: Molecular Cell
• Volume: 53
• Issue: 2
• Start Page: 247
• End Page: 261
• Grant/Funding Information: This work is supported by funding from Stand Up to Cancer (SU2C), Leukemia and Lymphoma Society (LLS), Novartis Research Institute and National Institute of Health (NIH) to Y.D., from LLS to S.W., from Howard Hughes Medical Institute (HHMI) to M. L., and from NIH to S.M., Q.S and J.L.H.
• Keywords: Disruption; Complex; Inhibition; Biochemistry & Molecular Biology; Cell Biology; Domain; Science & Technology; Histone Methyltransferases; Protein; Hematopoiesis; Methylation; WDR5; Association; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology; Biology, Cell; Chemistry, Biochemistry

Abstract

Here we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research. © 2014 Elsevier Inc.